BRPI0608122A2 - composto, composição farmacêutica, e, uso da mesma - Google Patents
composto, composição farmacêutica, e, uso da mesma Download PDFInfo
- Publication number
- BRPI0608122A2 BRPI0608122A2 BRPI0608122-3A BRPI0608122A BRPI0608122A2 BR PI0608122 A2 BRPI0608122 A2 BR PI0608122A2 BR PI0608122 A BRPI0608122 A BR PI0608122A BR PI0608122 A2 BRPI0608122 A2 BR PI0608122A2
- Authority
- BR
- Brazil
- Prior art keywords
- alkyl
- cycloalkyl
- pyridin
- morpholin
- dimethyl
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 188
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 22
- 238000011282 treatment Methods 0.000 claims abstract description 26
- 108020001213 potassium channel Proteins 0.000 claims abstract description 20
- 102000004257 Potassium Channel Human genes 0.000 claims abstract description 19
- 125000000217 alkyl group Chemical group 0.000 claims description 158
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 64
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 62
- -1 2,4-dimethyl-6-morpholin-4-yl-pyridin-3-yl Chemical group 0.000 claims description 50
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 47
- 150000003839 salts Chemical class 0.000 claims description 39
- 206010010904 Convulsion Diseases 0.000 claims description 36
- 229910052736 halogen Inorganic materials 0.000 claims description 27
- 208000035475 disorder Diseases 0.000 claims description 26
- 208000019901 Anxiety disease Diseases 0.000 claims description 25
- 125000001424 substituent group Chemical group 0.000 claims description 23
- 239000012458 free base Substances 0.000 claims description 22
- 150000002367 halogens Chemical class 0.000 claims description 22
- 201000010099 disease Diseases 0.000 claims description 21
- 206010015037 epilepsy Diseases 0.000 claims description 21
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 17
- 208000004296 neuralgia Diseases 0.000 claims description 17
- 208000021722 neuropathic pain Diseases 0.000 claims description 17
- 239000002253 acid Substances 0.000 claims description 14
- 125000005843 halogen group Chemical group 0.000 claims description 14
- 125000003107 substituted aryl group Chemical group 0.000 claims description 13
- 208000015122 neurodegenerative disease Diseases 0.000 claims description 12
- 208000019695 Migraine disease Diseases 0.000 claims description 11
- 206010027599 migraine Diseases 0.000 claims description 11
- 230000001537 neural effect Effects 0.000 claims description 10
- 239000000126 substance Substances 0.000 claims description 10
- 229910052799 carbon Inorganic materials 0.000 claims description 9
- 208000002193 Pain Diseases 0.000 claims description 8
- 230000036506 anxiety Effects 0.000 claims description 8
- 239000003085 diluting agent Substances 0.000 claims description 8
- 230000004770 neurodegeneration Effects 0.000 claims description 8
- 208000027520 Somatoform disease Diseases 0.000 claims description 7
- 239000001257 hydrogen Substances 0.000 claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 208000027753 pain disease Diseases 0.000 claims description 7
- 208000019906 panic disease Diseases 0.000 claims description 7
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 6
- 206010001497 Agitation Diseases 0.000 claims description 6
- 208000008811 Agoraphobia Diseases 0.000 claims description 6
- 206010036105 Polyneuropathy Diseases 0.000 claims description 6
- 210000003169 central nervous system Anatomy 0.000 claims description 6
- 150000002500 ions Chemical class 0.000 claims description 6
- 208000020925 Bipolar disease Diseases 0.000 claims description 5
- 206010034912 Phobia Diseases 0.000 claims description 5
- 201000001716 specific phobia Diseases 0.000 claims description 5
- 230000001037 epileptic effect Effects 0.000 claims description 4
- ZINNHCARUJQQRJ-UHFFFAOYSA-N 4-(4,6-dimethylpyridin-2-yl)morpholine Chemical compound CC1=CC(C)=NC(N2CCOCC2)=C1 ZINNHCARUJQQRJ-UHFFFAOYSA-N 0.000 claims description 3
- 208000030507 AIDS Diseases 0.000 claims description 3
- 208000024827 Alzheimer disease Diseases 0.000 claims description 3
- 208000014644 Brain disease Diseases 0.000 claims description 3
- 208000022497 Cocaine-Related disease Diseases 0.000 claims description 3
- 208000010859 Creutzfeldt-Jakob disease Diseases 0.000 claims description 3
- 206010013654 Drug abuse Diseases 0.000 claims description 3
- 208000032274 Encephalopathy Diseases 0.000 claims description 3
- 208000011688 Generalised anxiety disease Diseases 0.000 claims description 3
- 208000023105 Huntington disease Diseases 0.000 claims description 3
- 208000004454 Hyperalgesia Diseases 0.000 claims description 3
- 206010029240 Neuritis Diseases 0.000 claims description 3
- 208000021384 Obsessive-Compulsive disease Diseases 0.000 claims description 3
- 208000018737 Parkinson disease Diseases 0.000 claims description 3
- 241000710799 Rubella virus Species 0.000 claims description 3
- 208000000810 Separation Anxiety Diseases 0.000 claims description 3
- 208000013738 Sleep Initiation and Maintenance disease Diseases 0.000 claims description 3
- 208000007271 Substance Withdrawal Syndrome Diseases 0.000 claims description 3
- 208000009205 Tinnitus Diseases 0.000 claims description 3
- 206010070863 Toxicity to various agents Diseases 0.000 claims description 3
- 208000026345 acute stress disease Diseases 0.000 claims description 3
- 208000012826 adjustment disease Diseases 0.000 claims description 3
- 208000029650 alcohol withdrawal Diseases 0.000 claims description 3
- 206010053552 allodynia Diseases 0.000 claims description 3
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 claims description 3
- 239000000969 carrier Substances 0.000 claims description 3
- 201000001272 cocaine abuse Diseases 0.000 claims description 3
- 150000002148 esters Chemical class 0.000 claims description 3
- 230000004907 flux Effects 0.000 claims description 3
- 208000029364 generalized anxiety disease Diseases 0.000 claims description 3
- 230000000917 hyperalgesic effect Effects 0.000 claims description 3
- 208000014674 injury Diseases 0.000 claims description 3
- 206010022437 insomnia Diseases 0.000 claims description 3
- 201000006417 multiple sclerosis Diseases 0.000 claims description 3
- 244000052769 pathogen Species 0.000 claims description 3
- 210000001428 peripheral nervous system Anatomy 0.000 claims description 3
- 208000019629 polyneuritis Diseases 0.000 claims description 3
- 230000007824 polyneuropathy Effects 0.000 claims description 3
- 208000028173 post-traumatic stress disease Diseases 0.000 claims description 3
- 208000020016 psychiatric disease Diseases 0.000 claims description 3
- 208000025874 separation anxiety disease Diseases 0.000 claims description 3
- 208000019116 sleep disease Diseases 0.000 claims description 3
- 231100000886 tinnitus Toxicity 0.000 claims description 3
- 230000008733 trauma Effects 0.000 claims description 3
- 241001529453 unidentified herpesvirus Species 0.000 claims description 3
- SNICXCGAKADSCV-JTQLQIEISA-N (-)-Nicotine Chemical compound CN1CCC[C@H]1C1=CC=CN=C1 SNICXCGAKADSCV-JTQLQIEISA-N 0.000 claims description 2
- CKYXLLATWNDTOC-UHFFFAOYSA-N 2-(3,4-dichlorophenyl)-n-(2,4-dimethyl-6-morpholin-4-ylpyridin-3-yl)acetamide Chemical compound CC1=CC(N2CCOCC2)=NC(C)=C1NC(=O)CC1=CC=C(Cl)C(Cl)=C1 CKYXLLATWNDTOC-UHFFFAOYSA-N 0.000 claims description 2
- LTYGQAJETYOFCA-UHFFFAOYSA-N 2-(3-bromophenyl)-n-(2,4-dimethyl-6-morpholin-4-ylpyridin-3-yl)acetamide Chemical compound CC1=CC(N2CCOCC2)=NC(C)=C1NC(=O)CC1=CC=CC(Br)=C1 LTYGQAJETYOFCA-UHFFFAOYSA-N 0.000 claims description 2
- MEPMQOPXUQHOJD-UHFFFAOYSA-N 2-(cyclohexen-1-yl)-n-(2,4-dimethyl-6-morpholin-4-ylpyridin-3-yl)acetamide Chemical compound CC1=CC(N2CCOCC2)=NC(C)=C1NC(=O)CC1=CCCCC1 MEPMQOPXUQHOJD-UHFFFAOYSA-N 0.000 claims description 2
- ZWODLPCPFZMMPF-UHFFFAOYSA-N 2-cyclopentyl-n-(2,4-dimethyl-6-morpholin-4-ylpyridin-3-yl)acetamide Chemical compound CC1=CC(N2CCOCC2)=NC(C)=C1NC(=O)CC1CCCC1 ZWODLPCPFZMMPF-UHFFFAOYSA-N 0.000 claims description 2
- 241000589968 Borrelia Species 0.000 claims description 2
- 208000032131 Diabetic Neuropathies Diseases 0.000 claims description 2
- 208000002877 Epileptic Syndromes Diseases 0.000 claims description 2
- 241000725303 Human immunodeficiency virus Species 0.000 claims description 2
- 208000016604 Lyme disease Diseases 0.000 claims description 2
- 241000124008 Mammalia Species 0.000 claims description 2
- 206010033664 Panic attack Diseases 0.000 claims description 2
- 206010041250 Social phobia Diseases 0.000 claims description 2
- 208000006011 Stroke Diseases 0.000 claims description 2
- 208000031674 Traumatic Acute Stress disease Diseases 0.000 claims description 2
- 230000001154 acute effect Effects 0.000 claims description 2
- 230000035987 intoxication Effects 0.000 claims description 2
- 231100000566 intoxication Toxicity 0.000 claims description 2
- QFXOZVHCESXJLE-UHFFFAOYSA-N n-(2,4-dimethyl-6-morpholin-4-ylpyridin-3-yl)-2-(3,5-dimethylphenyl)acetamide Chemical compound CC1=CC(C)=CC(CC(=O)NC=2C(=NC(=CC=2C)N2CCOCC2)C)=C1 QFXOZVHCESXJLE-UHFFFAOYSA-N 0.000 claims description 2
- LNHWKNMHQDEDHA-UHFFFAOYSA-N n-(2,4-dimethyl-6-morpholin-4-ylpyridin-3-yl)-2-(3-fluorophenyl)acetamide Chemical compound CC1=CC(N2CCOCC2)=NC(C)=C1NC(=O)CC1=CC=CC(F)=C1 LNHWKNMHQDEDHA-UHFFFAOYSA-N 0.000 claims description 2
- LXXQJPDIABMXEO-UHFFFAOYSA-N n-(2,4-dimethyl-6-morpholin-4-ylpyridin-3-yl)-2-(4-fluorophenyl)acetamide Chemical compound CC1=CC(N2CCOCC2)=NC(C)=C1NC(=O)CC1=CC=C(F)C=C1 LXXQJPDIABMXEO-UHFFFAOYSA-N 0.000 claims description 2
- BKFDFCVASNKPOA-UHFFFAOYSA-N n-(2,4-dimethyl-6-morpholin-4-ylpyridin-3-yl)-3,3-dimethylbutanamide Chemical compound CC1=C(NC(=O)CC(C)(C)C)C(C)=CC(N2CCOCC2)=N1 BKFDFCVASNKPOA-UHFFFAOYSA-N 0.000 claims description 2
- JXZMYIPYHBOYME-UHFFFAOYSA-N n-(2-chloro-4-methoxy-6-morpholin-4-ylpyridin-3-yl)-2-cyclopentylacetamide Chemical compound COC1=CC(N2CCOCC2)=NC(Cl)=C1NC(=O)CC1CCCC1 JXZMYIPYHBOYME-UHFFFAOYSA-N 0.000 claims description 2
- FNGCWQBVWMPXRW-UHFFFAOYSA-N n-(4-chloro-2-methoxy-6-morpholin-4-ylpyridin-3-yl)propanamide Chemical compound N1=C(OC)C(NC(=O)CC)=C(Cl)C=C1N1CCOCC1 FNGCWQBVWMPXRW-UHFFFAOYSA-N 0.000 claims description 2
- 229960002715 nicotine Drugs 0.000 claims description 2
- SNICXCGAKADSCV-UHFFFAOYSA-N nicotine Natural products CN1CCCC1C1=CC=CN=C1 SNICXCGAKADSCV-UHFFFAOYSA-N 0.000 claims description 2
- 206010044652 trigeminal neuralgia Diseases 0.000 claims description 2
- 230000009385 viral infection Effects 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 2
- PVKGAFIBJUZLPW-UHFFFAOYSA-N 3-cyclohexyl-n-(2,4-dimethyl-6-morpholin-4-ylpyridin-3-yl)propanamide Chemical compound CC1=CC(N2CCOCC2)=NC(C)=C1NC(=O)CCC1CCCCC1 PVKGAFIBJUZLPW-UHFFFAOYSA-N 0.000 claims 1
- RPFWGJBXQZHWJN-UHFFFAOYSA-N CCCCC(C1=C(N=C(C=C1C)N2CCOCC2)C)C(=O)N Chemical compound CCCCC(C1=C(N=C(C=C1C)N2CCOCC2)C)C(=O)N RPFWGJBXQZHWJN-UHFFFAOYSA-N 0.000 claims 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims 1
- MNWFXJYAOYHMED-UHFFFAOYSA-N heptanoic acid group Chemical group C(CCCCCC)(=O)O MNWFXJYAOYHMED-UHFFFAOYSA-N 0.000 claims 1
- MTXSFPSKHDODED-UHFFFAOYSA-N n-(2,4-dimethyl-6-morpholin-4-ylpyridin-3-yl)-2-(3-methylphenyl)acetamide Chemical compound CC1=CC=CC(CC(=O)NC=2C(=NC(=CC=2C)N2CCOCC2)C)=C1 MTXSFPSKHDODED-UHFFFAOYSA-N 0.000 claims 1
- ZWAWWLRQLGIARH-UHFFFAOYSA-N n-(2,4-dimethyl-6-morpholin-4-ylpyridin-3-yl)-2-(4-methoxyphenyl)acetamide Chemical compound C1=CC(OC)=CC=C1CC(=O)NC1=C(C)C=C(N2CCOCC2)N=C1C ZWAWWLRQLGIARH-UHFFFAOYSA-N 0.000 claims 1
- ZZQZQXDYSRXASP-UHFFFAOYSA-N n-(2,4-dimethyl-6-morpholin-4-ylpyridin-3-yl)-2-(4-methylphenyl)acetamide Chemical compound C1=CC(C)=CC=C1CC(=O)NC1=C(C)C=C(N2CCOCC2)N=C1C ZZQZQXDYSRXASP-UHFFFAOYSA-N 0.000 claims 1
- LOCRXXVELNBLQE-UHFFFAOYSA-N n-(2,4-dimethyl-6-morpholin-4-ylpyridin-3-yl)-2-phenylacetamide Chemical compound CC1=CC(N2CCOCC2)=NC(C)=C1NC(=O)CC1=CC=CC=C1 LOCRXXVELNBLQE-UHFFFAOYSA-N 0.000 claims 1
- KAKNMOGUWPXQFL-UHFFFAOYSA-N n-(2,4-dimethyl-6-morpholin-4-ylpyridin-3-yl)-3-(4-methoxyphenyl)propanamide Chemical compound C1=CC(OC)=CC=C1CCC(=O)NC1=C(C)C=C(N2CCOCC2)N=C1C KAKNMOGUWPXQFL-UHFFFAOYSA-N 0.000 claims 1
- BLESCNKLEXGCBO-UHFFFAOYSA-N n-(2,4-dimethyl-6-morpholin-4-ylpyridin-3-yl)-4-methylpentanamide Chemical compound N1=C(C)C(NC(=O)CCC(C)C)=C(C)C=C1N1CCOCC1 BLESCNKLEXGCBO-UHFFFAOYSA-N 0.000 claims 1
- 230000002981 neuropathic effect Effects 0.000 claims 1
- 229940080818 propionamide Drugs 0.000 claims 1
- 150000003222 pyridines Chemical class 0.000 abstract description 3
- 208000015114 central nervous system disease Diseases 0.000 abstract 1
- 238000000105 evaporative light scattering detection Methods 0.000 description 51
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 49
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 42
- 108010006746 KCNQ2 Potassium Channel Proteins 0.000 description 38
- 102000005453 KCNQ2 Potassium Channel Human genes 0.000 description 31
- 238000000034 method Methods 0.000 description 28
- 238000005160 1H NMR spectroscopy Methods 0.000 description 26
- 230000000694 effects Effects 0.000 description 23
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 22
- 238000002360 preparation method Methods 0.000 description 19
- 239000000243 solution Substances 0.000 description 19
- 239000002904 solvent Substances 0.000 description 19
- 238000012360 testing method Methods 0.000 description 19
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 18
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 18
- PCOBBVZJEWWZFR-UHFFFAOYSA-N ezogabine Chemical compound C1=C(N)C(NC(=O)OCC)=CC=C1NCC1=CC=C(F)C=C1 PCOBBVZJEWWZFR-UHFFFAOYSA-N 0.000 description 17
- 239000000203 mixture Substances 0.000 description 17
- 108091006146 Channels Proteins 0.000 description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
- 229960003312 retigabine Drugs 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 14
- 238000006243 chemical reaction Methods 0.000 description 13
- 239000011541 reaction mixture Substances 0.000 description 13
- 239000007787 solid Substances 0.000 description 13
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 13
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 12
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 12
- 230000001773 anti-convulsant effect Effects 0.000 description 12
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 11
- 239000003814 drug Substances 0.000 description 11
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 10
- 239000001961 anticonvulsive agent Substances 0.000 description 10
- 229960003965 antiepileptics Drugs 0.000 description 10
- 239000002585 base Substances 0.000 description 10
- 125000004432 carbon atom Chemical group C* 0.000 description 10
- 239000012074 organic phase Substances 0.000 description 10
- 239000011591 potassium Substances 0.000 description 10
- 229910052700 potassium Inorganic materials 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- 108010038888 KCNQ3 Potassium Channel Proteins 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 9
- 210000004027 cell Anatomy 0.000 description 9
- LPMZGLWTJXFVTO-UHFFFAOYSA-N 2,4-dimethyl-6-morpholin-4-ylpyridin-3-amine Chemical compound CC1=C(N)C(C)=CC(N2CCOCC2)=N1 LPMZGLWTJXFVTO-UHFFFAOYSA-N 0.000 description 8
- 101000994656 Homo sapiens Potassium voltage-gated channel subfamily KQT member 5 Proteins 0.000 description 8
- 102000015686 KCNQ3 Potassium Channel Human genes 0.000 description 8
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 8
- 229940079593 drug Drugs 0.000 description 8
- 239000011734 sodium Substances 0.000 description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 7
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical class [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 7
- 241001465754 Metazoa Species 0.000 description 7
- 230000004913 activation Effects 0.000 description 7
- 210000004556 brain Anatomy 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- 238000010992 reflux Methods 0.000 description 7
- 239000003826 tablet Substances 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- 102100034365 Potassium voltage-gated channel subfamily KQT member 5 Human genes 0.000 description 6
- 239000004480 active ingredient Substances 0.000 description 6
- 229910052786 argon Inorganic materials 0.000 description 6
- 238000006880 cross-coupling reaction Methods 0.000 description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 6
- 235000019341 magnesium sulphate Nutrition 0.000 description 6
- 239000012528 membrane Substances 0.000 description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
- 230000003287 optical effect Effects 0.000 description 6
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 6
- 229910052708 sodium Inorganic materials 0.000 description 6
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 6
- QCHFTSOMWOSFHM-WPRPVWTQSA-N (+)-Pilocarpine Chemical compound C1OC(=O)[C@@H](CC)[C@H]1CC1=CN=CN1C QCHFTSOMWOSFHM-WPRPVWTQSA-N 0.000 description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 5
- 241000699666 Mus <mouse, genus> Species 0.000 description 5
- 241000699670 Mus sp. Species 0.000 description 5
- CWRVKFFCRWGWCS-UHFFFAOYSA-N Pentrazole Chemical compound C1CCCCC2=NN=NN21 CWRVKFFCRWGWCS-UHFFFAOYSA-N 0.000 description 5
- 241000700159 Rattus Species 0.000 description 5
- QCHFTSOMWOSFHM-UHFFFAOYSA-N SJ000285536 Natural products C1OC(=O)C(CC)C1CC1=CN=CN1C QCHFTSOMWOSFHM-UHFFFAOYSA-N 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 125000003118 aryl group Chemical group 0.000 description 5
- 239000003054 catalyst Substances 0.000 description 5
- 238000007333 cyanation reaction Methods 0.000 description 5
- 229960001760 dimethyl sulfoxide Drugs 0.000 description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 5
- 238000009472 formulation Methods 0.000 description 5
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 5
- 230000000670 limiting effect Effects 0.000 description 5
- 238000002483 medication Methods 0.000 description 5
- 238000006396 nitration reaction Methods 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- 229960001416 pilocarpine Drugs 0.000 description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 description 5
- 108090000623 proteins and genes Proteins 0.000 description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 5
- XDMRHYVTLFVRSW-UHFFFAOYSA-N 4-(4-chloro-6-methoxy-5-nitropyridin-2-yl)morpholine Chemical compound ClC1=C([N+]([O-])=O)C(OC)=NC(N2CCOCC2)=C1 XDMRHYVTLFVRSW-UHFFFAOYSA-N 0.000 description 4
- CJGYIHZNIXBLMM-UHFFFAOYSA-N 4-(6-chloro-4-methoxy-5-nitropyridin-2-yl)morpholine Chemical compound ClC1=C([N+]([O-])=O)C(OC)=CC(N2CCOCC2)=N1 CJGYIHZNIXBLMM-UHFFFAOYSA-N 0.000 description 4
- UGJMXCAKCUNAIE-UHFFFAOYSA-N Gabapentin Chemical compound OC(=O)CC1(CN)CCCCC1 UGJMXCAKCUNAIE-UHFFFAOYSA-N 0.000 description 4
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 4
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 4
- 125000003342 alkenyl group Chemical group 0.000 description 4
- 210000004978 chinese hamster ovary cell Anatomy 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 4
- 125000001072 heteroaryl group Chemical group 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 238000007912 intraperitoneal administration Methods 0.000 description 4
- 229910052744 lithium Inorganic materials 0.000 description 4
- 125000002950 monocyclic group Chemical group 0.000 description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 229940002612 prodrug Drugs 0.000 description 4
- 239000000651 prodrug Substances 0.000 description 4
- VWDWKYIASSYTQR-UHFFFAOYSA-N sodium nitrate Chemical compound [Na+].[O-][N+]([O-])=O VWDWKYIASSYTQR-UHFFFAOYSA-N 0.000 description 4
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 239000006188 syrup Substances 0.000 description 4
- 235000020357 syrup Nutrition 0.000 description 4
- 125000005270 trialkylamine group Chemical group 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- 229910004298 SiO 2 Inorganic materials 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 229960000583 acetic acid Drugs 0.000 description 3
- 239000000654 additive Substances 0.000 description 3
- 239000002671 adjuvant Substances 0.000 description 3
- 210000004727 amygdala Anatomy 0.000 description 3
- 125000002619 bicyclic group Chemical group 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 239000012267 brine Substances 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 150000001721 carbon Chemical group 0.000 description 3
- CURLTUGMZLYLDI-UHFFFAOYSA-N carbon dioxide Natural products O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 229910052681 coesite Inorganic materials 0.000 description 3
- 229910052906 cristobalite Inorganic materials 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 239000003937 drug carrier Substances 0.000 description 3
- 239000012039 electrophile Substances 0.000 description 3
- 238000010828 elution Methods 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 238000003818 flash chromatography Methods 0.000 description 3
- 229910052731 fluorine Inorganic materials 0.000 description 3
- 125000005842 heteroatom Chemical group 0.000 description 3
- 230000006872 improvement Effects 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 238000007918 intramuscular administration Methods 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- 239000000395 magnesium oxide Substances 0.000 description 3
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 description 3
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 description 3
- 108020004999 messenger RNA Proteins 0.000 description 3
- 150000007522 mineralic acids Chemical class 0.000 description 3
- 230000035772 mutation Effects 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 235000019198 oils Nutrition 0.000 description 3
- 210000000287 oocyte Anatomy 0.000 description 3
- 150000007524 organic acids Chemical class 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- 229960005152 pentetrazol Drugs 0.000 description 3
- 230000003389 potentiating effect Effects 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 102000005962 receptors Human genes 0.000 description 3
- 108020003175 receptors Proteins 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 238000012552 review Methods 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- 229910052682 stishovite Inorganic materials 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- 231100001274 therapeutic index Toxicity 0.000 description 3
- AXZWODMDQAVCJE-UHFFFAOYSA-L tin(II) chloride (anhydrous) Chemical compound [Cl-].[Cl-].[Sn+2] AXZWODMDQAVCJE-UHFFFAOYSA-L 0.000 description 3
- 229910052905 tridymite Inorganic materials 0.000 description 3
- 239000003643 water by type Substances 0.000 description 3
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 2
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- IZHVBANLECCAGF-UHFFFAOYSA-N 2-hydroxy-3-(octadecanoyloxy)propyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)COC(=O)CCCCCCCCCCCCCCCCC IZHVBANLECCAGF-UHFFFAOYSA-N 0.000 description 2
- BIESNLWMYKMSOC-UHFFFAOYSA-N 4-(4,6-dichloro-5-nitropyridin-2-yl)morpholine Chemical compound N1=C(Cl)C([N+](=O)[O-])=C(Cl)C=C1N1CCOCC1 BIESNLWMYKMSOC-UHFFFAOYSA-N 0.000 description 2
- DEAXCAUYSPNKPN-UHFFFAOYSA-N 4-(4,6-dichloropyridin-2-yl)morpholine Chemical compound ClC1=CC(Cl)=NC(N2CCOCC2)=C1 DEAXCAUYSPNKPN-UHFFFAOYSA-N 0.000 description 2
- NGMNFXMTMMZYOG-UHFFFAOYSA-N 4-(4,6-dimethyl-5-nitropyridin-2-yl)morpholine Chemical compound CC1=C([N+]([O-])=O)C(C)=CC(N2CCOCC2)=N1 NGMNFXMTMMZYOG-UHFFFAOYSA-N 0.000 description 2
- MHPUGCYGQWGLJL-UHFFFAOYSA-N 5-methyl-hexanoic acid Chemical compound CC(C)CCCC(O)=O MHPUGCYGQWGLJL-UHFFFAOYSA-N 0.000 description 2
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 2
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 2
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 2
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 description 2
- 206010011878 Deafness Diseases 0.000 description 2
- 239000012981 Hank's balanced salt solution Substances 0.000 description 2
- 101000994648 Homo sapiens Potassium voltage-gated channel subfamily KQT member 4 Proteins 0.000 description 2
- 102000004310 Ion Channels Human genes 0.000 description 2
- 108090000862 Ion Channels Proteins 0.000 description 2
- 102000012359 KCNQ Potassium Channels Human genes 0.000 description 2
- 108010022282 KCNQ Potassium Channels Proteins 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- HOKKHZGPKSLGJE-GSVOUGTGSA-N N-Methyl-D-aspartic acid Chemical compound CN[C@@H](C(O)=O)CC(O)=O HOKKHZGPKSLGJE-GSVOUGTGSA-N 0.000 description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical class O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 2
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 235000019483 Peanut oil Nutrition 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- 229940127315 Potassium Channel Openers Drugs 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- PQLVXDKIJBQVDF-UHFFFAOYSA-N acetic acid;hydrate Chemical compound O.CC(O)=O PQLVXDKIJBQVDF-UHFFFAOYSA-N 0.000 description 2
- 230000036982 action potential Effects 0.000 description 2
- 125000000304 alkynyl group Chemical group 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 2
- 150000003863 ammonium salts Chemical class 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 230000002082 anti-convulsion Effects 0.000 description 2
- 230000002059 anti-epileptogenic effect Effects 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 230000001977 ataxic effect Effects 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 230000006399 behavior Effects 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 description 2
- 125000000480 butynyl group Chemical group [*]C#CC([H])([H])C([H])([H])[H] 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 229910002092 carbon dioxide Inorganic materials 0.000 description 2
- 150000001244 carboxylic acid anhydrides Chemical class 0.000 description 2
- 150000001735 carboxylic acids Chemical class 0.000 description 2
- 239000003638 chemical reducing agent Substances 0.000 description 2
- 230000001276 controlling effect Effects 0.000 description 2
- 230000036461 convulsion Effects 0.000 description 2
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 description 2
- 230000027326 copulation Effects 0.000 description 2
- 125000000392 cycloalkenyl group Chemical group 0.000 description 2
- 231100000895 deafness Toxicity 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 230000003111 delayed effect Effects 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 206010013663 drug dependence Diseases 0.000 description 2
- 150000002170 ethers Chemical class 0.000 description 2
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 2
- 230000005284 excitation Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 229960002870 gabapentin Drugs 0.000 description 2
- 229960003692 gamma aminobutyric acid Drugs 0.000 description 2
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 2
- 239000007903 gelatin capsule Substances 0.000 description 2
- 230000014509 gene expression Effects 0.000 description 2
- 239000012362 glacial acetic acid Substances 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 229940093915 gynecological organic acid Drugs 0.000 description 2
- 208000016354 hearing loss disease Diseases 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- 125000004366 heterocycloalkenyl group Chemical group 0.000 description 2
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 230000000971 hippocampal effect Effects 0.000 description 2
- 150000002431 hydrogen Chemical class 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 230000002631 hypothermal effect Effects 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 2
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 2
- 230000010354 integration Effects 0.000 description 2
- 238000007913 intrathecal administration Methods 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 2
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 2
- 229940011051 isopropyl acetate Drugs 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 2
- 229910000103 lithium hydride Inorganic materials 0.000 description 2
- WMFOQBRAJBCJND-UHFFFAOYSA-M lithium hydroxide Inorganic materials [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 2
- 230000006742 locomotor activity Effects 0.000 description 2
- 208000004731 long QT syndrome Diseases 0.000 description 2
- 210000003141 lower extremity Anatomy 0.000 description 2
- 239000007937 lozenge Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Chemical class 0.000 description 2
- 238000006263 metalation reaction Methods 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 230000008587 neuronal excitability Effects 0.000 description 2
- 229910052759 nickel Inorganic materials 0.000 description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 125000004430 oxygen atom Chemical group O* 0.000 description 2
- 210000002741 palatine tonsil Anatomy 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- 239000000312 peanut oil Substances 0.000 description 2
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 230000035479 physiological effects, processes and functions Effects 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- 239000004036 potassium channel stimulating agent Substances 0.000 description 2
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 2
- 229910000105 potassium hydride Inorganic materials 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 230000002035 prolonged effect Effects 0.000 description 2
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 2
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- 235000009518 sodium iodide Nutrition 0.000 description 2
- 239000004317 sodium nitrate Substances 0.000 description 2
- 235000010344 sodium nitrate Nutrition 0.000 description 2
- 235000010288 sodium nitrite Nutrition 0.000 description 2
- 238000010561 standard procedure Methods 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 208000011117 substance-related disease Diseases 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 238000001356 surgical procedure Methods 0.000 description 2
- HJUGFYREWKUQJT-UHFFFAOYSA-N tetrabromomethane Chemical compound BrC(Br)(Br)Br HJUGFYREWKUQJT-UHFFFAOYSA-N 0.000 description 2
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 230000001256 tonic effect Effects 0.000 description 2
- 150000003852 triazoles Chemical class 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 2
- FHZUOZWUOXJEHV-UHFFFAOYSA-N (2-chlorophenyl)methyl n-(2,4-dimethyl-6-morpholin-4-ylpyridin-3-yl)carbamate Chemical compound CC1=CC(N2CCOCC2)=NC(C)=C1NC(=O)OCC1=CC=CC=C1Cl FHZUOZWUOXJEHV-UHFFFAOYSA-N 0.000 description 1
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 description 1
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 1
- 125000006621 (C3-C8) cycloalkyl-(C1-C6) alkyl group Chemical group 0.000 description 1
- MUCYRGGMVNGLNP-UHFFFAOYSA-N 1-benzofuran;1-benzothiophene Chemical compound C1=CC=C2OC=CC2=C1.C1=CC=C2SC=CC2=C1 MUCYRGGMVNGLNP-UHFFFAOYSA-N 0.000 description 1
- SVUOLADPCWQTTE-UHFFFAOYSA-N 1h-1,2-benzodiazepine Chemical compound N1N=CC=CC2=CC=CC=C12 SVUOLADPCWQTTE-UHFFFAOYSA-N 0.000 description 1
- OXBLVCZKDOZZOJ-UHFFFAOYSA-N 2,3-Dihydrothiophene Chemical compound C1CC=CS1 OXBLVCZKDOZZOJ-UHFFFAOYSA-N 0.000 description 1
- JKTCBAGSMQIFNL-UHFFFAOYSA-N 2,3-dihydrofuran Chemical compound C1CC=CO1 JKTCBAGSMQIFNL-UHFFFAOYSA-N 0.000 description 1
- FJNNGKMAGDPVIU-UHFFFAOYSA-N 2,4,6-trichloropyridine Chemical compound ClC1=CC(Cl)=NC(Cl)=C1 FJNNGKMAGDPVIU-UHFFFAOYSA-N 0.000 description 1
- HCYFGRCYSCXKNQ-UHFFFAOYSA-N 2-(1,3-dimethyl-2,6-dioxo-7-purinyl)acetic acid Chemical compound O=C1N(C)C(=O)N(C)C2=C1N(CC(O)=O)C=N2 HCYFGRCYSCXKNQ-UHFFFAOYSA-N 0.000 description 1
- IWPAOTPPULTUIR-UHFFFAOYSA-N 2-(3-chlorophenyl)-n-(2,4-dimethyl-6-morpholin-4-ylpyridin-3-yl)acetamide Chemical compound CC1=CC(N2CCOCC2)=NC(C)=C1NC(=O)CC1=CC=CC(Cl)=C1 IWPAOTPPULTUIR-UHFFFAOYSA-N 0.000 description 1
- QKKSRAZNRMRSGA-UHFFFAOYSA-N 2-(4-chlorophenyl)-n-(2,4-dimethyl-6-morpholin-4-ylpyridin-3-yl)acetamide Chemical compound CC1=CC(N2CCOCC2)=NC(C)=C1NC(=O)CC1=CC=C(Cl)C=C1 QKKSRAZNRMRSGA-UHFFFAOYSA-N 0.000 description 1
- QEDVSHKCKCPZJX-UHFFFAOYSA-N 2-chloro-4-methoxy-6-morpholin-4-ylpyridin-3-amine Chemical compound ClC1=C(N)C(OC)=CC(N2CCOCC2)=N1 QEDVSHKCKCPZJX-UHFFFAOYSA-N 0.000 description 1
- NILLIUYSJFTTRH-UHFFFAOYSA-N 2-cyclopentylacetyl chloride Chemical compound ClC(=O)CC1CCCC1 NILLIUYSJFTTRH-UHFFFAOYSA-N 0.000 description 1
- NNJPKMLLSQRIQX-UHFFFAOYSA-N 2-methylpropyl n-(2,4-dimethyl-6-morpholin-4-ylpyridin-3-yl)carbamate Chemical compound N1=C(C)C(NC(=O)OCC(C)C)=C(C)C=C1N1CCOCC1 NNJPKMLLSQRIQX-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- OESDYULIRWTQIK-UHFFFAOYSA-N 3-(3-chlorophenyl)-n-(2,4-dimethyl-6-morpholin-4-ylpyridin-3-yl)propanamide Chemical compound CC1=CC(N2CCOCC2)=NC(C)=C1NC(=O)CCC1=CC=CC(Cl)=C1 OESDYULIRWTQIK-UHFFFAOYSA-N 0.000 description 1
- CLTDVBQNUHHYCA-UHFFFAOYSA-N 3-(3-chlorophenyl)propanoic acid Chemical compound OC(=O)CCC1=CC=CC(Cl)=C1 CLTDVBQNUHHYCA-UHFFFAOYSA-N 0.000 description 1
- WHTGDXHISJRNKN-UHFFFAOYSA-N 3-cyclopentyl-n-(2,4-dimethyl-6-morpholin-4-ylpyridin-3-yl)propanamide Chemical compound CC1=CC(N2CCOCC2)=NC(C)=C1NC(=O)CCC1CCCC1 WHTGDXHISJRNKN-UHFFFAOYSA-N 0.000 description 1
- GJMPSRSMBJLKKB-UHFFFAOYSA-N 3-methylphenylacetic acid Chemical compound CC1=CC=CC(CC(O)=O)=C1 GJMPSRSMBJLKKB-UHFFFAOYSA-N 0.000 description 1
- BRBUBVKGJRPRRD-UHFFFAOYSA-N 4,6-dimethylpyridin-2-amine Chemical compound CC1=CC(C)=NC(N)=C1 BRBUBVKGJRPRRD-UHFFFAOYSA-N 0.000 description 1
- PXSPLZGLKGQCIU-UHFFFAOYSA-N 4-chloro-2-methoxy-6-morpholin-4-ylpyridin-3-amine Chemical compound ClC1=C(N)C(OC)=NC(N2CCOCC2)=C1 PXSPLZGLKGQCIU-UHFFFAOYSA-N 0.000 description 1
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- SKTFQHRVFFOHTQ-UHFFFAOYSA-N 8-bromo-1,3-dimethyl-7h-purine-2,6-dione Chemical compound O=C1N(C)C(=O)N(C)C2=C1NC(Br)=N2 SKTFQHRVFFOHTQ-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 244000105624 Arachis hypogaea Species 0.000 description 1
- ZNSMNVMLTJELDZ-UHFFFAOYSA-N Bis(2-chloroethyl)ether Chemical compound ClCCOCCCl ZNSMNVMLTJELDZ-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- GAWIXWVDTYZWAW-UHFFFAOYSA-N C[CH]O Chemical group C[CH]O GAWIXWVDTYZWAW-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 108090000312 Calcium Channels Proteins 0.000 description 1
- 102000003922 Calcium Channels Human genes 0.000 description 1
- WWZKQHOCKIZLMA-UHFFFAOYSA-N Caprylic acid Natural products CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 208000033001 Complex partial seizures Diseases 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- 206010011882 Deafness congenital Diseases 0.000 description 1
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 1
- 206010061818 Disease progression Diseases 0.000 description 1
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical compound [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 201000001916 Hypochondriasis Diseases 0.000 description 1
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 1
- 108010011185 KCNQ1 Potassium Channel Proteins 0.000 description 1
- 101150074326 Kcnq3 gene Proteins 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical class [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 238000006751 Mitsunobu reaction Methods 0.000 description 1
- 101100399296 Mus musculus Lime1 gene Proteins 0.000 description 1
- 102000004868 N-Methyl-D-Aspartate Receptors Human genes 0.000 description 1
- 108090001041 N-Methyl-D-Aspartate Receptors Proteins 0.000 description 1
- PHSPJQZRQAJPPF-UHFFFAOYSA-N N-alpha-Methylhistamine Chemical compound CNCCC1=CN=CN1 PHSPJQZRQAJPPF-UHFFFAOYSA-N 0.000 description 1
- 150000001204 N-oxides Chemical class 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 206010033668 Panic disorder without agoraphobia Diseases 0.000 description 1
- 208000004983 Phantom Limb Diseases 0.000 description 1
- 206010056238 Phantom pain Diseases 0.000 description 1
- CXOFVDLJLONNDW-UHFFFAOYSA-N Phenytoin Chemical compound N1C(=O)NC(=O)C1(C=1C=CC=CC=1)C1=CC=CC=C1 CXOFVDLJLONNDW-UHFFFAOYSA-N 0.000 description 1
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical class ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- LHNKBXRFNPMIBR-UHFFFAOYSA-N Picrotoxin Natural products CC(C)(O)C1(O)C2OC(=O)C1C3(O)C4OC4C5C(=O)OC2C35C LHNKBXRFNPMIBR-UHFFFAOYSA-N 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 102100037444 Potassium voltage-gated channel subfamily KQT member 1 Human genes 0.000 description 1
- 102100034363 Potassium voltage-gated channel subfamily KQT member 4 Human genes 0.000 description 1
- 208000034189 Sclerosis Diseases 0.000 description 1
- 108010052164 Sodium Channels Proteins 0.000 description 1
- 102000018674 Sodium Channels Human genes 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 238000003477 Sonogashira cross-coupling reaction Methods 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 231100000643 Substance intoxication Toxicity 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 229910021626 Tin(II) chloride Inorganic materials 0.000 description 1
- KJADKKWYZYXHBB-XBWDGYHZSA-N Topiramic acid Chemical compound C1O[C@@]2(COS(N)(=O)=O)OC(C)(C)O[C@H]2[C@@H]2OC(C)(C)O[C@@H]21 KJADKKWYZYXHBB-XBWDGYHZSA-N 0.000 description 1
- 229930003427 Vitamin E Natural products 0.000 description 1
- 206010048010 Withdrawal syndrome Diseases 0.000 description 1
- 241000269370 Xenopus <genus> Species 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- DSVGQVZAZSZEEX-UHFFFAOYSA-N [C].[Pt] Chemical class [C].[Pt] DSVGQVZAZSZEEX-UHFFFAOYSA-N 0.000 description 1
- GPWHDDKQSYOYBF-UHFFFAOYSA-N ac1l2u0q Chemical compound Br[Br-]Br GPWHDDKQSYOYBF-UHFFFAOYSA-N 0.000 description 1
- 229950003769 acefylline Drugs 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 235000010419 agar Nutrition 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 150000001337 aliphatic alkines Chemical class 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 150000001345 alkine derivatives Chemical class 0.000 description 1
- 150000001347 alkyl bromides Chemical class 0.000 description 1
- 150000001348 alkyl chlorides Chemical class 0.000 description 1
- 150000005215 alkyl ethers Chemical class 0.000 description 1
- 150000001351 alkyl iodides Chemical class 0.000 description 1
- 125000005233 alkylalcohol group Chemical group 0.000 description 1
- VLSMHEGGTFMBBZ-UHFFFAOYSA-N alpha-Kainic acid Natural products CC(=C)C1CNC(C(O)=O)C1CC(O)=O VLSMHEGGTFMBBZ-UHFFFAOYSA-N 0.000 description 1
- VREFGVBLTWBCJP-UHFFFAOYSA-N alprazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NN=C2CN=C1C1=CC=CC=C1 VREFGVBLTWBCJP-UHFFFAOYSA-N 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 210000004102 animal cell Anatomy 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 230000006400 anxiety behaviour Effects 0.000 description 1
- 230000007529 anxiety like behavior Effects 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 238000007080 aromatic substitution reaction Methods 0.000 description 1
- 230000037007 arousal Effects 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 210000001130 astrocyte Anatomy 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000001746 atrial effect Effects 0.000 description 1
- 210000003030 auditory receptor cell Anatomy 0.000 description 1
- ZSIQJIWKELUFRJ-UHFFFAOYSA-N azepane Chemical compound C1CCCNCC1 ZSIQJIWKELUFRJ-UHFFFAOYSA-N 0.000 description 1
- 229940125717 barbiturate Drugs 0.000 description 1
- HNYOPLTXPVRDBG-UHFFFAOYSA-N barbituric acid Chemical compound O=C1CC(=O)NC(=O)N1 HNYOPLTXPVRDBG-UHFFFAOYSA-N 0.000 description 1
- 201000003452 benign familial neonatal epilepsy Diseases 0.000 description 1
- 201000010295 benign neonatal seizures Diseases 0.000 description 1
- RFRXIWQYSOIBDI-UHFFFAOYSA-N benzarone Chemical compound CCC=1OC2=CC=CC=C2C=1C(=O)C1=CC=C(O)C=C1 RFRXIWQYSOIBDI-UHFFFAOYSA-N 0.000 description 1
- 229940049706 benzodiazepine Drugs 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 1
- KAEMILXLUFFLSU-UHFFFAOYSA-N benzyl n-(2,4-dimethyl-6-morpholin-4-ylpyridin-3-yl)carbamate Chemical compound CC1=CC(N2CCOCC2)=NC(C)=C1NC(=O)OCC1=CC=CC=C1 KAEMILXLUFFLSU-UHFFFAOYSA-N 0.000 description 1
- GONOPSZTUGRENK-UHFFFAOYSA-N benzyl(trichloro)silane Chemical compound Cl[Si](Cl)(Cl)CC1=CC=CC=C1 GONOPSZTUGRENK-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 1
- 229960000623 carbamazepine Drugs 0.000 description 1
- FFGPTBGBLSHEPO-UHFFFAOYSA-N carbamazepine Chemical compound C1=CC2=CC=CC=C2N(C(=O)N)C2=CC=CC=C21 FFGPTBGBLSHEPO-UHFFFAOYSA-N 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- MOIPGXQKZSZOQX-UHFFFAOYSA-N carbonyl bromide Chemical class BrC(Br)=O MOIPGXQKZSZOQX-UHFFFAOYSA-N 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 239000012159 carrier gas Substances 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 238000000451 chemical ionisation Methods 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- VEZNCHDBSQWUHQ-UHFFFAOYSA-N chlorocyclopropane Chemical compound ClC1CC1 VEZNCHDBSQWUHQ-UHFFFAOYSA-N 0.000 description 1
- 230000001713 cholinergic effect Effects 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 208000028502 clonic seizure Diseases 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 230000036757 core body temperature Effects 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 229940099112 cornstarch Drugs 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- WZHCOOQXZCIUNC-UHFFFAOYSA-N cyclandelate Chemical compound C1C(C)(C)CC(C)CC1OC(=O)C(O)C1=CC=CC=C1 WZHCOOQXZCIUNC-UHFFFAOYSA-N 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- ARUKYTASOALXFG-UHFFFAOYSA-N cycloheptylcycloheptane Chemical group C1CCCCCC1C1CCCCCC1 ARUKYTASOALXFG-UHFFFAOYSA-N 0.000 description 1
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 230000006735 deficit Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 239000007933 dermal patch Substances 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- NIJJYAXOARWZEE-UHFFFAOYSA-N di-n-propyl-acetic acid Natural products CCCC(C(O)=O)CCC NIJJYAXOARWZEE-UHFFFAOYSA-N 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- 230000005750 disease progression Effects 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 230000003291 dopaminomimetic effect Effects 0.000 description 1
- 210000003027 ear inner Anatomy 0.000 description 1
- 238000000537 electroencephalography Methods 0.000 description 1
- 238000007345 electrophilic aromatic substitution reaction Methods 0.000 description 1
- 230000008918 emotional behaviour Effects 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 238000009505 enteric coating Methods 0.000 description 1
- HAPOVYFOVVWLRS-UHFFFAOYSA-N ethosuximide Chemical compound CCC1(C)CC(=O)NC1=O HAPOVYFOVVWLRS-UHFFFAOYSA-N 0.000 description 1
- 230000002461 excitatory amino acid Effects 0.000 description 1
- 239000003257 excitatory amino acid Substances 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 description 1
- 210000000609 ganglia Anatomy 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 238000011686 genetic mapping animal model Methods 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 229940074045 glyceryl distearate Drugs 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- 125000001475 halogen functional group Chemical group 0.000 description 1
- 239000001307 helium Substances 0.000 description 1
- 229910052734 helium Inorganic materials 0.000 description 1
- SWQJXJOGLNCZEY-UHFFFAOYSA-N helium atom Chemical compound [He] SWQJXJOGLNCZEY-UHFFFAOYSA-N 0.000 description 1
- 238000009904 heterogeneous catalytic hydrogenation reaction Methods 0.000 description 1
- VHHHONWQHHHLTI-UHFFFAOYSA-N hexachloroethane Chemical compound ClC(Cl)(Cl)C(Cl)(Cl)Cl VHHHONWQHHHLTI-UHFFFAOYSA-N 0.000 description 1
- 210000001320 hippocampus Anatomy 0.000 description 1
- 210000005260 human cell Anatomy 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 230000002102 hyperpolarization Effects 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 230000000415 inactivating effect Effects 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- VLSMHEGGTFMBBZ-OOZYFLPDSA-N kainic acid Chemical compound CC(=C)[C@H]1CN[C@H](C(O)=O)[C@H]1CC(O)=O VLSMHEGGTFMBBZ-OOZYFLPDSA-N 0.000 description 1
- 229950006874 kainic acid Drugs 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229960001848 lamotrigine Drugs 0.000 description 1
- PYZRQGJRPPTADH-UHFFFAOYSA-N lamotrigine Chemical compound NC1=NC(N)=NN=C1C1=CC=CC(Cl)=C1Cl PYZRQGJRPPTADH-UHFFFAOYSA-N 0.000 description 1
- 229960004002 levetiracetam Drugs 0.000 description 1
- HPHUVLMMVZITSG-ZCFIWIBFSA-N levetiracetam Chemical compound CC[C@H](C(N)=O)N1CCCC1=O HPHUVLMMVZITSG-ZCFIWIBFSA-N 0.000 description 1
- 230000002197 limbic effect Effects 0.000 description 1
- 239000008297 liquid dosage form Substances 0.000 description 1
- 239000006194 liquid suspension Substances 0.000 description 1
- 230000004807 localization Effects 0.000 description 1
- 239000011777 magnesium Chemical class 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000017813 membrane repolarization Effects 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical class C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000003607 modifier Substances 0.000 description 1
- UNFUYWDGSFDHCW-UHFFFAOYSA-N monochlorocyclohexane Chemical compound ClC1CCCCC1 UNFUYWDGSFDHCW-UHFFFAOYSA-N 0.000 description 1
- 230000004118 muscle contraction Effects 0.000 description 1
- NSXYSIRPQHZGRS-UHFFFAOYSA-N n-(2,4-dimethyl-6-morpholin-4-ylpyridin-3-yl)-2-(3,4-dimethylphenyl)acetamide Chemical compound C1=C(C)C(C)=CC=C1CC(=O)NC1=C(C)C=C(N2CCOCC2)N=C1C NSXYSIRPQHZGRS-UHFFFAOYSA-N 0.000 description 1
- RVOCAYGOJGYTFK-UHFFFAOYSA-N n-(2,4-dimethyl-6-morpholin-4-ylpyridin-3-yl)-2-(4-methoxy-3-methylphenyl)acetamide Chemical compound C1=C(C)C(OC)=CC=C1CC(=O)NC1=C(C)C=C(N2CCOCC2)N=C1C RVOCAYGOJGYTFK-UHFFFAOYSA-N 0.000 description 1
- OEMGVWLOWRPQLL-UHFFFAOYSA-N n-(2,4-dimethyl-6-morpholin-4-ylpyridin-3-yl)-2-[3-(trifluoromethyl)phenyl]acetamide Chemical compound CC1=CC(N2CCOCC2)=NC(C)=C1NC(=O)CC1=CC=CC(C(F)(F)F)=C1 OEMGVWLOWRPQLL-UHFFFAOYSA-N 0.000 description 1
- GKDVUJSUFGQXKA-UHFFFAOYSA-N n-(2,4-dimethyl-6-morpholin-4-ylpyridin-3-yl)-2-naphthalen-2-ylacetamide Chemical compound N=1C(C)=C(NC(=O)CC=2C=C3C=CC=CC3=CC=2)C(C)=CC=1N1CCOCC1 GKDVUJSUFGQXKA-UHFFFAOYSA-N 0.000 description 1
- MRNPWIWBKMYBTH-UHFFFAOYSA-N n-(2,4-dimethyl-6-morpholin-4-ylpyridin-3-yl)-2-phenylcyclopropane-1-carboxamide Chemical compound CC1=CC(N2CCOCC2)=NC(C)=C1NC(=O)C1CC1C1=CC=CC=C1 MRNPWIWBKMYBTH-UHFFFAOYSA-N 0.000 description 1
- VRDZAGWZCGIZSC-UHFFFAOYSA-N n-(2,4-dimethyl-6-morpholin-4-ylpyridin-3-yl)-2-thiophen-2-ylacetamide Chemical compound CC1=CC(N2CCOCC2)=NC(C)=C1NC(=O)CC1=CC=CS1 VRDZAGWZCGIZSC-UHFFFAOYSA-N 0.000 description 1
- ZBQQCPVAXQILBE-UHFFFAOYSA-N n-(2,4-dimethyl-6-morpholin-4-ylpyridin-3-yl)-2-thiophen-3-ylacetamide Chemical compound CC1=CC(N2CCOCC2)=NC(C)=C1NC(=O)CC=1C=CSC=1 ZBQQCPVAXQILBE-UHFFFAOYSA-N 0.000 description 1
- OFNMXZJAGVKVKO-UHFFFAOYSA-N n-(2,4-dimethyl-6-morpholin-4-ylpyridin-3-yl)-3-(4-methylphenyl)propanamide Chemical compound C1=CC(C)=CC=C1CCC(=O)NC1=C(C)C=C(N2CCOCC2)N=C1C OFNMXZJAGVKVKO-UHFFFAOYSA-N 0.000 description 1
- RZPBJOUKSLGPAK-UHFFFAOYSA-N n-(2,4-dimethyl-6-morpholin-4-ylpyridin-3-yl)heptanamide Chemical compound N1=C(C)C(NC(=O)CCCCCC)=C(C)C=C1N1CCOCC1 RZPBJOUKSLGPAK-UHFFFAOYSA-N 0.000 description 1
- QHRDANBBSJKUAT-UHFFFAOYSA-N n-(2,4-dimethyl-6-morpholin-4-ylpyridin-3-yl)octanamide Chemical compound N1=C(C)C(NC(=O)CCCCCCC)=C(C)C=C1N1CCOCC1 QHRDANBBSJKUAT-UHFFFAOYSA-N 0.000 description 1
- CTONPIFXRWAMMT-UHFFFAOYSA-N n-(4-chloro-2-methoxy-6-morpholin-4-ylpyridin-3-yl)-2-cyclopentylacetamide Chemical compound COC1=NC(N2CCOCC2)=CC(Cl)=C1NC(=O)CC1CCCC1 CTONPIFXRWAMMT-UHFFFAOYSA-N 0.000 description 1
- OSHLKYWGTPRHND-UHFFFAOYSA-N n-(4-chloro-2-methoxy-6-morpholin-4-ylpyridin-3-yl)-3,3-dimethylbutanamide Chemical compound ClC1=C(NC(=O)CC(C)(C)C)C(OC)=NC(N2CCOCC2)=C1 OSHLKYWGTPRHND-UHFFFAOYSA-N 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N n-hexanoic acid Natural products CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 230000036403 neuro physiology Effects 0.000 description 1
- 230000000626 neurodegenerative effect Effects 0.000 description 1
- 210000004498 neuroglial cell Anatomy 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 230000008555 neuronal activation Effects 0.000 description 1
- 230000003961 neuronal insult Effects 0.000 description 1
- 201000001119 neuropathy Diseases 0.000 description 1
- 230000007823 neuropathy Effects 0.000 description 1
- 230000000324 neuroprotective effect Effects 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000007764 o/w emulsion Substances 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-N palmitic acid group Chemical group C(CCCCCCCCCCCCCCC)(=O)O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 238000010647 peptide synthesis reaction Methods 0.000 description 1
- 208000033808 peripheral neuropathy Diseases 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
- 229960002036 phenytoin Drugs 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- VJKUPQSHOVKBCO-AHMKVGDJSA-N picrotoxin Chemical compound O=C([C@@]12O[C@@H]1C[C@]1(O)[C@@]32C)O[C@@H]3[C@H]2[C@@H](C(=C)C)[C@@H]1C(=O)O2.O=C([C@@]12O[C@@H]1C[C@]1(O)[C@@]32C)O[C@@H]3[C@H]2[C@@H](C(C)(O)C)[C@@H]1C(=O)O2 VJKUPQSHOVKBCO-AHMKVGDJSA-N 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 238000007747 plating Methods 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 229960001233 pregabalin Drugs 0.000 description 1
- AYXYPKUFHZROOJ-ZETCQYMHSA-N pregabalin Chemical compound CC(C)C[C@H](CN)CC(O)=O AYXYPKUFHZROOJ-ZETCQYMHSA-N 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 210000001176 projection neuron Anatomy 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000036390 resting membrane potential Effects 0.000 description 1
- 238000010825 rotarod performance test Methods 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 239000000932 sedative agent Substances 0.000 description 1
- 230000001624 sedative effect Effects 0.000 description 1
- 230000031893 sensory processing Effects 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 239000010865 sewage Substances 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 239000002356 single layer Substances 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- JVBXVOWTABLYPX-UHFFFAOYSA-L sodium dithionite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])=O JVBXVOWTABLYPX-UHFFFAOYSA-L 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- AEQFSUDEHCCHBT-UHFFFAOYSA-M sodium valproate Chemical compound [Na+].CCCC(C([O-])=O)CCC AEQFSUDEHCCHBT-UHFFFAOYSA-M 0.000 description 1
- 229940084026 sodium valproate Drugs 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 238000012453 sprague-dawley rat model Methods 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 230000010473 stable expression Effects 0.000 description 1
- 235000011150 stannous chloride Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 230000000946 synaptic effect Effects 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- QEMXHQIAXOOASZ-UHFFFAOYSA-N tetramethylammonium Chemical class C[N+](C)(C)C QEMXHQIAXOOASZ-UHFFFAOYSA-N 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 229960004394 topiramate Drugs 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- 125000004665 trialkylsilyl group Chemical group 0.000 description 1
- 125000005106 triarylsilyl group Chemical group 0.000 description 1
- 210000000836 trigeminal nuclei Anatomy 0.000 description 1
- 210000004496 type 1 vestibular hair cell Anatomy 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 230000002861 ventricular Effects 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
- 239000007762 w/o emulsion Substances 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- NWONKYPBYAMBJT-UHFFFAOYSA-L zinc sulfate Chemical compound [Zn+2].[O-]S([O-])(=O)=O NWONKYPBYAMBJT-UHFFFAOYSA-L 0.000 description 1
- 229960002911 zonisamide Drugs 0.000 description 1
- UBQNRHZMVUUOMG-UHFFFAOYSA-N zonisamide Chemical compound C1=CC=C2C(CS(=O)(=O)N)=NOC2=C1 UBQNRHZMVUUOMG-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DKPA200500321 | 2005-03-03 | ||
| DKPA200500321 | 2005-03-03 | ||
| PCT/DK2006/000123 WO2006092143A1 (en) | 2005-03-03 | 2006-03-02 | Substituted pyridine derivatives |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| BRPI0608122A2 true BRPI0608122A2 (pt) | 2010-11-09 |
Family
ID=37908541
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| BRPI0608122-3A BRPI0608122A2 (pt) | 2005-03-03 | 2006-03-02 | composto, composição farmacêutica, e, uso da mesma |
Country Status (13)
| Country | Link |
|---|---|
| KR (2) | KR20070108884A (es) |
| CN (3) | CN101133053A (es) |
| AR (1) | AR052931A1 (es) |
| BR (1) | BRPI0608122A2 (es) |
| DK (1) | DK2298766T3 (es) |
| EA (1) | EA016244B1 (es) |
| ES (1) | ES2433593T3 (es) |
| IL (1) | IL185113A (es) |
| NZ (1) | NZ556613A (es) |
| PT (1) | PT2298766E (es) |
| SI (1) | SI2298766T1 (es) |
| UA (1) | UA92340C2 (es) |
| ZA (1) | ZA200705987B (es) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114409593B (zh) * | 2022-01-20 | 2024-02-23 | 上海泾维化工科技有限公司 | 一种2-氨基-5-甲基吡啶的制备方法 |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ATE380176T1 (de) * | 1999-08-04 | 2007-12-15 | Icagen Inc | Benzanilide als öffner des kaliumkanals |
| NZ522794A (en) * | 2000-06-29 | 2005-04-29 | Neurosearch As | Use of 3-substituted oxindole derivatives as KCNQ potassium channel modulators |
| JP2005508833A (ja) * | 2001-02-20 | 2005-04-07 | ブリストル−マイヤーズ スクイブ カンパニー | Kcnqカリウムチャネル・モジュレーターとしての2,4−ジ置換ピリミジン−5−カルボキサミド誘導体 |
| EP1613303A1 (en) * | 2003-03-21 | 2006-01-11 | H. Lundbeck A/S | Substituted p-diaminobenzene derivatives |
| TWI357901B (en) * | 2004-03-12 | 2012-02-11 | Lundbeck & Co As H | Substituted morpholine and thiomorpholine derivati |
-
2006
- 2006-02-03 UA UAA200710648A patent/UA92340C2/ru unknown
- 2006-03-02 EA EA200701877A patent/EA016244B1/ru not_active IP Right Cessation
- 2006-03-02 CN CNA2006800068313A patent/CN101133053A/zh active Pending
- 2006-03-02 KR KR1020077019782A patent/KR20070108884A/ko not_active Ceased
- 2006-03-02 AR ARP060100790A patent/AR052931A1/es unknown
- 2006-03-02 KR KR1020137019572A patent/KR20130088905A/ko not_active Ceased
- 2006-03-02 CN CN201110168073.8A patent/CN102276523B/zh not_active Expired - Fee Related
- 2006-03-02 NZ NZ556613A patent/NZ556613A/en not_active IP Right Cessation
- 2006-03-02 ES ES10182072T patent/ES2433593T3/es not_active Expired - Lifetime
- 2006-03-02 CN CN2011103097414A patent/CN102516165A/zh active Pending
- 2006-03-02 SI SI200631682T patent/SI2298766T1/sl unknown
- 2006-03-02 BR BRPI0608122-3A patent/BRPI0608122A2/pt not_active IP Right Cessation
- 2006-03-02 PT PT101820728T patent/PT2298766E/pt unknown
- 2006-03-02 DK DK10182072.8T patent/DK2298766T3/da active
- 2006-03-02 ZA ZA200705987A patent/ZA200705987B/xx unknown
-
2007
- 2007-08-07 IL IL185113A patent/IL185113A/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| PT2298766E (pt) | 2013-11-07 |
| IL185113A (en) | 2013-10-31 |
| EA200701877A1 (ru) | 2008-02-28 |
| EA016244B1 (ru) | 2012-03-30 |
| IL185113A0 (en) | 2007-12-03 |
| UA92340C2 (en) | 2010-10-25 |
| CN102276523A (zh) | 2011-12-14 |
| DK2298766T3 (da) | 2013-11-11 |
| SI2298766T1 (sl) | 2014-05-30 |
| AR052931A1 (es) | 2007-04-11 |
| KR20130088905A (ko) | 2013-08-08 |
| CN101133053A (zh) | 2008-02-27 |
| KR20070108884A (ko) | 2007-11-13 |
| ZA200705987B (en) | 2009-05-27 |
| CN102276523B (zh) | 2014-12-10 |
| HK1164868A1 (en) | 2012-09-28 |
| NZ556613A (en) | 2010-11-26 |
| CN102516165A (zh) | 2012-06-27 |
| ES2433593T3 (es) | 2013-12-11 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP5237643B2 (ja) | 置換されたピリジン誘導体 | |
| JP5006184B2 (ja) | 置換されたモルホリンおよびチオモルホリン誘導体 | |
| US20100137311A1 (en) | Substituted pyrimidine derivatives | |
| US20060264496A1 (en) | Substituted indoline and indole derivatives | |
| WO2002012189A1 (en) | Fused bicyclic amide compounds and medicinal use thereof | |
| BRPI0615631A2 (pt) | composto, composição farmacêutica, e, uso de uma composição farmacêutica | |
| BRPI0608122A2 (pt) | composto, composição farmacêutica, e, uso da mesma | |
| HRP20080507A2 (hr) | Supstituirani derivati morfolina i tiomorfolina | |
| MXPA06010329A (es) | Derivados sustituidos de morfolina y tiomorfolina | |
| HK1122273A (en) | Pyrimidine derivatives and their use as kcnq potassium channels openers |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| B06G | Technical and formal requirements: other requirements [chapter 6.7 patent gazette] |
Free format text: SOLICITA-SE A REGULARIZACAO DA PROCURACAO, UMA VEZ QUE BASEADO NO ARTIGO 216 1O DA LPI, O DOCUMENTO DE PROCURACAO DEVE SER APRESENTADO NO ORIGINAL, TRASLADO OU FOTOCOPIA AUTENTICADA. |
|
| B08F | Application dismissed because of non-payment of annual fees [chapter 8.6 patent gazette] |
Free format text: REFERENTE A 10A ANUIDADE. |
|
| B08K | Patent lapsed as no evidence of payment of the annual fee has been furnished to inpi [chapter 8.11 patent gazette] |
Free format text: EM VIRTUDE DO ARQUIVAMENTO PUBLICADO NA RPI 2366 DE 10-05-2016 E CONSIDERANDO AUSENCIA DE MANIFESTACAO DENTRO DOS PRAZOS LEGAIS, INFORMO QUE CABE SER MANTIDO O ARQUIVAMENTO DO PEDIDO DE PATENTE, CONFORME O DISPOSTO NO ARTIGO 12, DA RESOLUCAO 113/2013. |